Abstract The overall goals of this project are to combine novel concepts in synthetic biology with an in-depth understanding of chondrocyte mechanobiology to develop tissue-engineered constructs that contain synthetic mechanogenetic gene circuits. The primary aim of this project will be to generate ?smart? tissue-engineered cartilage constructs that feature cell-based, feedback control of gene expression as a means of autoregulated drug or growth factor delivery, based on the mechanical loading environment. To engineer this regulatory system, the gene regulation circuitry of chondrocytes will be rewired to form controlled feedback loops that are activated by external mechanical stimuli to induce a self-regulating anti-inflammatory response. The initial focus of the project will be on the creation of designer cells that contain artificial gene circuits that provide anti- cytokine drug delivery in response to differing levels of mechanical loading. The creation of artificial mechanogenetic gene circuits in cells will provide a novel means of self-regulating drug therapy as a transformative paradigm for regenerative medicine.